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UroGenRA™-Kidney Array-CGH Assay for the diagnosis and subtyping of renal cortical neoplasms INFORM UroGenRA™-Kidney aCGH assesses multiple genomic biomarker sets providing more information than other common methods.

PREDICT KidneyPath™ assists in determining proper renal tumor subtype.

CLIA and New York State Approved For more information, please visit www.cancergenetics.com

DECIDE Together with other clinical and laboratory findings, UroGenRA™-Kidney can assist in devising the best treatment plan for an individual patient.


Kidney Cancer Approximately 65,000 new cases of kidney cancer and about 13,500 deaths from the disease occur in the U.S. each year [1]. Renal cell carcinoma (RCC) is the most abundant and lethal form of kidney cancer. There are three main subtypes of RCC: clear cell (ccRCC), papillary (pRCC), and chromophobe (chrRCC). The next most frequent renal cortical neoplasm is oncocytoma (OC), which is benign and can be followed by active surveillance. Choice of therapy depends upon the kidney cancer subtype as well as the patient’s age and comorbidities. Despite advancements in the diagnosis of renal tumors in recent years, the mortality rate of localized RCC (Stage I and II) is steadily increasing. Surgical intervention is the standard treatment. However, active surveillance may be recommended to patients who are unfit for surgical intervention or have a limited life expectancy [3]. In addition, patients with benign neoplasms are often subjected to nephrectomy likely because current imaging techniques are limited in distinguishing whether a small renal mass (SRM) is benign or malignant. Nephrectomy may predispose patients to chronic kidney disease, increased cardiovascular risk and shortened overall survival [2]. Difficulties can also arise in the differential diagnosis of chrRCC (malignant) versus OC (benign) when selecting whether or not to perform surgery. Thus accurate diagnosis and subtyping can better differentiate those patients with benign renal neoplasms and SRMs who are eligible for active surveillance and can avoid overtreatment.

Malignant Renal Cortical Neoplasms Clear Cell (ccRCC) 60-65%

Papillary (pRCC) 13-15%

Chromophobe (chrRCC) 6%

Localized

Metastatic

Benign Renal Cortical Neoplasms

Nephrectomy

Nephrectomy & Systemic Therapy

Oncocytoma (OC) 6-9%

Active Surveillance

Over the years, specific genetic alterations have been associated with the four main renal cortical neoplasm subtypes. For instance, alteration of the Von Hippel-Lindau (VHL) gene has been suggested to be a pathogenetic event in ccRCC. Trisomy of chromosomes 7 and 17 are frequently observed in pRCC, and widespread monosomies in chrRCC. OC display a nearly diploid genome with loss of chromosome 1, 14 and Y. Therefore, genomic imbalance may be used to classify renal neoplasm subtypes. The UroGenRA™-Kidney Array-CGH provides genomic diagnostic information to assist routine histology in the subtyping of ccRCC, pRCC, chrRCC and OC from either core needle biopsies or resected specimens. This genomic assessment can give information to properly select the best treatment strategy and can prevent unnecessary surgical intervention.

The TheProcess Processof ofArray-CGH Array-CGH 1

2

Patient and control DNA labeled with fluorescent dyes are applied to the microarray.

CONTROL DNA

PATIENT DNA

Patient and control DNA are hybridized to the microarray.

3

4 DNA DOSAGE

DNA GAIN

DNA LOSS

The fluorescent signals are measured by the microarray scanner.

Next, the data is analyzed by computer software which then generates a plot.

NO CHANGE

© 2013 CANCER GENETICS, INC.


UroGenRA™ - Kidney Array-CGH Assay In a Single Test, UroGenRA™-Kidney Provides Genomic Data for the Histologic Classification of Renal Masses INFORM

PREDICT

DECIDE TM

KidneyPath

Treatment Selection

UroGenRA™ • UroGenRA™ has 101 regions of the human genome represented at an average resolution of 41.5kbp. • Regions covered by UroGenRA™ can be used for gain/loss evaluation in urogenital neoplasms including kidney, prostate and bladder cancers.

UroGenRA™-Kidney • UroGenRA™-Kidney assesses 16 genomic aberrations that have diagnostic significance in the four main renal cortical neoplasm subtypes. • UroGenRA™-Kidney can use DNA from either core needle biopsies or resected specimens, both provided as fresh frozen tissue.

KidneyPath™ Results from UroGenRA™-Kidney are analyzed using CGI’s proprietary algorithm, KidneyPath™. Specimens classified “normal” by the decision tree are reflexed to FISH (CCND1 break apart) in order to rule in/out OC subtype. Validated using: • Over 100 fresh frozen RCC specimens (surgically-resected) and needle biopsy specimens (MSKCC). • Publicly available data & published literature. • The Cancer Genome Atlas (TCGA) database, >500 specimens.

Key: Specific Genomic Aberration Yes - Genomic Aberration Is Present No - Genomic Aberration Is Not Present

cc p chr OC other normal RCC

References: 1. The American Cancer Society. www.cancer.org 2. Smaldone, M.C., et al., Small Renal Masses Progressing to Metastases Under Active Surveillance. Cancer Cell: 2012, 118(4): 9997-1006. 3. Heuer, R., et al., A Critical Analysis of theh Actual Role of Minimally Invasive Surgery and Active Surveillance for Kidney Cancer. European Urology: 2010, 57(2): 223-232. 4. The Cancer Genome Atlas. National Instittutes of Health. cancergenome.nih.gov

Proper Subtyping and Treatment Selection


Sample Report Assay Specifications

Sensitivity Limit of detection is 40% (assay sensitivity). Specimen Requirements For both biopsies and resected specimens, a minimum of 70% tumor population is preferred. Biopsy: Min. 3-4 needle/core biopsies (18-gauge needle) placed in a cryovial containing saline, transport frozen. Resected specimen: A minimum of 0.2x0.2x0.2cm tissue, snap-frozen in a cryovial and transported in frozen condition. CPT Code: 81479 Turnaround Time: 10-14 days

UroGenRA™ - Kidney Array-CGH Report Results:

Genomic Aberration

Result for Aberration

Genomic Aberration

Result for Aberration

Loss of VHL (chr3: 10.1-10.2 Mb)

POSITIVE

Gain of chr3

NEGATIVE

Loss of chr2

NEGATIVE

Loss of 6p25-q25

NEGATIVE

Gain of 17q12-q25

NEGATIVE

Loss of 10p15-q25

NEGATIVE

Gain of chr7

NEGATIVE

Loss of chr17

NEGATIVE

Gain of chr12

NEGATIVE

Loss of 8p (1-5, 19-27 Mb)

NEGATIVE

Gain of 16p13-p12

NEGATIVE

Loss of 1p36-q42

NEGATIVE

Gain of 20q13

NEGATIVE

Loss of 3p21.2-21.31

NEGATIVE

Gain of 5q (171-181 Mb)

POSITIVE

Loss of 21q22

NEGATIVE

Loss of VHL (chr3: 10.1-10.2 Mb)

Yes

Loss of chr17

P No

L

E

Gain of 17q

No

Clear Cell Renal Cell Carcinoma

Interpretation:

Genomic alterations detected are consistent with the diagnosis of Clear Cell Renal Cell Carcinoma.

Description:

The gain and loss of specific genomic regions associated with RCC subtypes are considered to have diagnostic value and aid in their classification. Loss of VHL gene at the 3p25 locus is a hallmark for clear cell RCC subtype.1-2 Gains of chromosomes 7 and 17 are frequently observed in papillary RCC and widespread monosomies (especially loss of chromosomes 2, 6, 10 and 17) are found in chromophobe RCC.2-4 Oncocytoma display a nearly diploid genome with loss of chromosome 1 or loss of 3p21.

A

M

This assay utilizes microarray-based comparative genomic hybridization (array CGH) to simultaneously detect the gain and loss of multiple loci in specimen DNA using the human genome build GRCh37/hg19. The sensitivity of the assay is 40%. Samples in which the tumor cells are present at less than 40%, aberrations may not be detected. The results of this study are to be interpreted in context with other clinical and/or histopathological findings. References:

S

1. Klatte, T., et al., Cytogenetic profile predicts prognosis of patients with clear cell renal cell carcinoma. J Clin Oncol, 2009. 27(5): p. 746-53. 2. Matsuda, D., et al., Identification of copy number alterations and its association with pathological features in clear cell and papillary RCC. Cancer Lett, 2008. 272(2): p. 260-7. 3. Klatte, T., et al., Cytogenetic and molecular tumor profiling for type 1 and type 2 papillary renal cell carcinoma. Clin Cancer Res, 2009. 15(4): p. 1162-9. 4. Krill-Burger, J.M., et al., Renal cell neoplasms contain shared tumor type-specific copy number variations. Am J Pathol, 2012. 180(6): p. 2427-39.

CGI Laboratory Licensure

CAP (Laboratory #: 7191582, AU-ID: 1434060), CLIA (Certificate #: 31D1038733), New Jersey (CLIS ID #: 0002299), New York State (PFI: 8192), Pennsylvania (031978), Florida (800018142), Maryland (1395). 201 Route 17 North • Rutherford • NJ 07070 • Office 201.528.9200 • Fax 201.528.9201 • www.cancergenetics.com © 2013 Cancer Genetics, Inc. All rights reserved.

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